The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination
- Author(s)
- Sijacki, T; Alcon, P; Chen, ZA; McLaughlin, SH; Shakeel, S; Rappsilber, J; Passmore, LA;
- Details
- Publication Year 2022-09,Volume 29,Issue #9,Page 881-890
- Journal Title
- Nature Structural & Molecular Biology
- Abstract
- DNA interstrand cross-links are tumor-inducing lesions that block DNA replication and transcription. When cross-links are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2-FANCI clamp by the Fanconi anemia core complex. Monoubiquitinated FANCD2-FANCI is locked onto DNA and recruits nucleases that mediate DNA repair. However, it remains unclear how phosphorylation activates this pathway. Here, we report structures of FANCD2-FANCI complexes containing phosphomimetic FANCI. We observe that, unlike wild-type FANCD2-FANCI, the phosphomimetic complex closes around DNA, independent of the Fanconi anemia core complex. The phosphomimetic mutations do not substantially alter DNA binding but instead destabilize the open state of FANCD2-FANCI and alter its conformational dynamics. Overall, our results demonstrate that phosphorylation primes the FANCD2-FANCI clamp for ubiquitination, showing how multiple posttranslational modifications are coordinated to control DNA repair.
- Publisher
- NPG
- Keywords
- Ataxia Telangiectasia Mutated Proteins/genetics/metabolism; DNA/metabolism; DNA Damage; DNA Repair; Fanconi Anemia/genetics; Fanconi Anemia Complementation Group D2 Protein/metabolism; Fanconi Anemia Complementation Group Proteins/genetics/metabolism; Humans; Polynucleotide 5'-Hydroxyl-Kinase/genetics/metabolism; Ubiquitination
- Research Division(s)
- Structural Biology
- PubMed ID
- 36050501
- Publisher's Version
- https://doi.org/10.1038/s41594-022-00820-9
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-02-02 02:06:38
Last Modified: 2023-02-17 11:19:34